Review Reports

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

1. Reactive ILVIP is an under-reported entity and only a handful of cases have been reported in the literature. The addition of two more adds to the importance of its recognition and distinction from the highly aggressive mimicker, intravascular lymphoma.
2. Line 42, the presence or absence of hepatosplenomegaly should be included, in addition to lympadenopathy.
3. Lines 58 and 59. This sentence about patient 2 has been wrongly inserted here.
4. Line 100. There was one more reported case of T-lineage ILVIP in an endometrial polyp. "Bryant A et al. Intravascular proliferation of reactive lymphoid blasts mimicking intravascular lymphoma - a diagnostic pitfall. Histopathology, 2007,51,401-402." which should also be cited. In fact, reference [6] should also be cited here.
5. Line 106. The same group of authors reported 12 cases in lymph nodes. which should be the largest series.  "Parisi X et al. Reactive intra-sinusoidal immunoblastic proliferations in lymph nodes: A Diagnostic Pitfall for diffuse large B-cell lymphoma. Lab Invest 2024,104(3):S1362-S1463."
6. In view of the conflicting findings in immunoglobulin gene rearrngement findings, some discussion on clonality of the immunobblastic proliferation should be included. (re: current refernces 4, 5 and the Histopathology reference suggested above).

Author Response

Comment 1: Reactive ILVIP is an under-reported entity and only a handful of cases have been reported in the literature. The addition of two more adds to the importance of its recognition and distinction from the highly aggressive mimicker, intravascular lymphoma.

Response 1: We thank the reviewer for this positive comment.

 

Comment 2: Line 42, the presence or absence of hepatosplenomegaly should be included, in addition to lymphadenopathy.

Response 2: Thank you for pointing this out. We have added information regarding hepatosplenomegaly and lymphadenopathy for both patients to define better their clinical presentations  (lines 54 and 73) and in Table 1.

 

Comment 3:  Lines 58 and 59. This sentence about patient 2 has been wrongly inserted here.

Response 3: Thank you for pointing this out. We have deleted an inappropriately placed sentence.

 

Comment 4: Line 100. There was one more reported case of T-lineage ILVIP in an endometrial polyp. "Bryant A et al. Intravascular proliferation of reactive lymphoid blasts mimicking intravascular lymphoma - a diagnostic pitfall. Histopathology, 2007,51,401-402." which should also be cited. In fact, reference [6] should also be cited here.

Response 4: Thank you for pointing this out. The suggested citation has been added, and reference numbering has been adjusted accordingly “atypical CD30-positive T-cell immunoblastic proliferations identified in conjunction with lichen sclerosis in foreskin biopsy a T-cell immunoblastic proliferation in an endometrial polyp” line 40 and “these immunoblasts most often exhibit B-cell lineage, although less common T-cell immunoblastic variants have also been described” lines 119-121.

 

Comment 5: Line 106. The same group of authors reported 12 cases in lymph nodes. which should be the largest series.  "Parisi X et al. Reactive intra-sinusoidal immunoblastic proliferations in lymph nodes: A Diagnostic Pitfall for diffuse large B-cell lymphoma. Lab Invest 2024,104(3):S1362-S1463."

Response 5: Thank you for pointing this out. We have incorporated this reference and noted that it represents the largest series to date “To date, the two largest series of ILVIP describe eight cases of B-cell lineage immunoblastic proliferation in gastrointestinal resection specimens and twelve cases involving lymph node sinuses” lines 120-122.

 

Comment 6: In view of the conflicting findings in immunoglobulin gene rearrangement findings, some discussion on the clonality of the immunoblastic proliferation should be included. (re: current references 4, 5 and the Histopathology reference suggested above).

Response 6: Thank you for pointing this out. We have added discussion on the immunoglobulin rearrangement “Rare cases with T-cell immunoblastic proliferations had immunoglobulin gene rearrangement, a finding of uncertain clinical significance” lines 39-41 and  “…no evidence of clonality, as judged by polytypic expression of kappa and lambda light chains and/or without clonal immunoglobulin gene rearrangement” lines 143-145.

Reviewer 2 Report

Comments and Suggestions for Authors

The authors described two cases of reactive intravascular B-cell immunoblastic proliferation (ILVIP) that mimics intravascular lymphoma.

The manuscript is interesting and adds existing evidence on ILVIP. However, several issues remain to be addressed.

1. In the Case reports section

• Although the authors mentioned in lines 41 and 42 in the Introduction section that “neither patient had lymphadenopathy or systemic findings”, lymphadenopathy was not described in patient 1 in the Case reports section.
• In lines 58 and 59, the authors stated that “The subset of immunoblasts was positive for CD3 and weak partial CD30 in patient 2.”Please verify whether this expression is correct.
• In lines 61 and 62, the authors said that ”B-cell clonality testing by PCR revealed no evidence of clonal IGH or IGK genes rearrangement. “Please indicate whether PCR for clonal IGH or IGK genes rearrangement was performed on the biopsy sample or any other specimen. Additionally, was flow cytometry used to assess immunoblasts clonality?
• Please provide additional information including treatment details of the patients to help clarify the clinical characteristics of ILVIP.

2. In the Discussion section

• Please provide a differential diagnosis between ILVIP and intravascular large B-cell lymphoma (IVLBCL).
• It is recommended to provide a brief literature review on ILVIP to enhance the manuscript’s clinical significance and readers’understanding of this entity.

Author Response

Comment 1: Although the authors mentioned in lines 41 and 42 in the Introduction section that “neither patient had lymphadenopathy or systemic findings”, lymphadenopathy was not described in patient 1 in the Case reports section.

Response 1: Thank you for pointing this out. We have clarified that patient 1 had no lymphadenopathy or systemic findings, ensuring consistency throughout the manuscript  “There was no lymphadenopathy, hepatosplenomegaly, fever, or night sweats” line 52.

 

Comment 2: In lines 58 and 59, the authors stated that “The subset of immunoblasts was positive for CD3 and weak partial CD30 in patient 2. ”Please verify whether this expression is correct.

Response 2: Thank you for pointing this out. We have deleted this inaccurate statement from description of Patient 1. This description belongs to Patient 2.

 

Comment 3:  In lines 61 and 62, the authors said that” B-cell clonality testing by PCR revealed no evidence of clonal IGH or IGK genes rearrangement. “Please indicate whether PCR for clonal IGH or IGK genes rearrangement was performed on the biopsy sample or any other specimen. Additionally, was flow cytometry used to assess immunoblasts clonality?

Response 3: Thank you for pointing this out.  We have added source of the tissue “section of colon with immunoblastic proliferation ”,  and added that “flow cytometry was not performed” lines 63-65 and “PCR-based clonality testing for IGH or IGK gene rearrangements and flow cytometry were not performed on the involved sections of the small bowel” lines 82.

 

Comment 4: Please provide additional information including treatment details of the patients to help clarify the clinical characteristics of ILVIP.

Response 4: Thank you for pointing this out. We have added description of treatment “Unfortunately, despite treatment with antibiotics, the patient died several weeks later from sepsis-related complications” lines 65-66 and “The patient was observed without systemic therapy and remains healthy” lines 85-86.

 

Comment 5: Please provide a differential diagnosis between ILVIP and intravascular     large B-cell lymphoma (IVLBCL).

Response 5: Thank you for pointing this out. We have added a differential diagnosis to indicate IVLBCL “The morphologic and immunophenotypic features of ILVIP may closely overlap with intravascular lymphoma or leukemia, with IVLBCL most concerning in immunoblasts with B-cell immunophenotype. Distinguishing ILVIP from IVLBCL is critical, as the latter is an aggressive malignancy requiring intensive chemotherapy and is associated with a poor prognosis, with a five-year overall survival rate of approximately 50% ” 114-118 lines and “These features contrast with intravascular large B-cell lymphoma, which typically shows extensive intravascular involvement, strong expression of B-cell markers such as CD20 and PAX5, light chain restriction, and clonal immunoglobulin rearrangement.  CD30, EBV, and HHV8 are usually negative in IVLBCL” lines 136-139.

 

 Comment 6: It is recommended to provide a brief literature review on ILVIP to enhance the manuscript’s clinical significance and readers’ understanding of this entity.

Response 6: Thank you for pointing this out. Introduction was updated to incorporate additional references to enhance the manuscript’s context and clinical relevance (lines 37-38). We have also added discussion on the clinical significance of ILVIP “To date, the largest two case series of ILVIP has documented 8 cases of B-cell immunoblastic intravascular proliferation identified in gastrointestinal resection samples and 12 cases in lymph nodes. Our two cases share a similar clinical presentation that parallels prior observations that ILVIP occurs most often in gastrointestinal specimens associated with infection, inflammation, or mechanical obstruction, suggesting that they represent a localized reactive response” 125-129 lines

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

The authors have addressed all my queries. I have no further comments.